Pediatric neoplasms are those which frequently arise in children. Examples of pediatric neoplasms include Wilms' tumor, neuroblastoma, retinoblastoma, leukemia, and tumors of the central nervous system (CNS). Common malignant pediatric tumors of the CNS include cerebellar astrocytomas and medulloblastomas, ependymomas, gliomas of the brain stem and optic nerve, germinomas, and congenital tumors. The most common metastatic tumors in children are neuroblastoma and leukemia (meningeal) (49).
Despite remarkable improvement in the survival rate of children with malignant disorders over the past two decades, cancer is still the second leading cause of death in children, after accidents (43). It has been estimated that more than 100,000 person-years of life are lost to pediatric cancer each year (44). While leukemia is the most common childhood cancer, estimates suggest that the incidences of certain other pediatric neoplasms, such as non-Hodgkin's lymphoma, neuroblastoma, glioma, primitive neuroectodermal tumor (PNET)/medulloblastoma, and other CNS tumors, have increased in recent decades (45).
Pediatric neoplasms are frequently embryonal neoplasms (i.e., neoplasms that originated during embryogenesis). Neuroblastoma, for example, is a solid malignant pediatric tumor that derives from the neural crest during development. It arises mainly in the adrenal gland, but also may arise from any portion of the extra-adrenal sympathetic chain, including the retroperitoneum and chest (49). Approximately 65% of neuroblastomas begin in the abdomen, and 15-20% begin in the thorax. The remaining 15% arise from various sites, including the neck and pelvis. Rarely, neuroblastoma can occur as a primary CNS tumor (49). Neuroblastoma is the most common extracranial tumor of childhood, and represents 10% of pediatric cancers. Approximately 75% of children with neuroblastomas are less than 5 years of age (49).
Amplification of the proto-oncogene N-myc is a common molecular finding in neuroblastoma. In approximately 30% of primary neuroblastomas, N-myc is amplified in multiple copies. N-myc amplification is associated with advanced disease and poor prognosis. Disseminated disease is also associated with poor prognosis. Common sites of dissemination include the bone, bone marrow, liver, lymph nodes, and skin (49). In approximately two-thirds of patients who have neuroblastoma, the disease is already disseminated at the time of diagnosis. Thus, there exists a need to develop strategies for earlier diagnosis.
Ultrasound and computed tomography are used to assess the nature and extent of the primary tumor in patients with neuroblastoma (49). At present, Stage I and Stage II neuroblastomas are treated by surgical excision of localized primary lesions. This treatment is successful in most cases. For Stage III and Stage IV neuroblastoma, where the disease has disseminated, therapy consists of intensive chemotherapeutic and radiation treatments. Chemotherapeutic drugs used to treat advanced disease include carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, and vincristine (49).
Better prognosis is indicated for children younger than one year, for children with a low stage of disease (Stage I or II), and for children in whom the tumor lacks amplification of the N-myc proto-oncogene (49). Poor prognosis is indicated for children older than one year, for children with advanced disease (Stage III or IV), and for children in whom the tumor shows amplification of N-myc. Prognosis is particularly poor for patients more than 1 year old who have an advanced stage of disease with amplification of N-myc, even with intensive treatment. Fewer than 20% of these patients survive five years post-diagnosis. Survival rates range from 30% to 40% for children with an advanced stage of disease but no N-myc amplification, and for children less than 1 year old who have an advanced stage of disease.
Retinoblastoma, another malignant pediatric tumor, arises from the immature retina (49). This pediatric neoplasm occurs in 1/15,000 to 1/30,000 live births, and represents about 2% of childhood malignancies. If diagnosed when the tumor is intraocular, more than 90% of patients can be cured. Unilateral retinoblastoma is managed by enucleation, with removal of as much of the optic nerve as possible. For those with bilateral disease, vision usually can be preserved with bilateral coagulation or unilateral enucleation and photocoagulation, cryotherapy, or radiation of the other eye. Systemic chemotherapy, such as carboplatin and etoposide, or cyclophosphamide and vincristine, may be helpful, particularly when the disease has disseminated beyond the globe (49).
Wilms' tumor, or nephroblastoma, is a malignant pediatric tumor of the kidney (49). It is composed of differing combinations of blastemal, epithelial, and stromal elements. Wilms' tumor generally presents in children under the age of 5, but sometimes may be found in older children. Prognosis depends upon the histologic appearance of the tumor, the stage at the time of diagnosis, and the age of the patient (with younger children having a more favorable prognosis). Prompt surgical exploration of potentially resectable lesions is generally carried out, along with examination of the contralateral kidney. Depending upon the stage of the disease, chemotherapy with actinomycin D and vincristine, either with or without radiation therapy, is used. Children with more advanced disease may also receive doxorubicin.
Despite the above-mentioned methods for detecting, diagnosing, and treating various pediatric neoplasms, cancer remains a significant factor in deaths of children under age 15. Successful management of pediatric neoplasms depends, in part, upon early detection of tumors. As with other cancers, a correlation exists between the tumor burden in a patient with a pediatric neoplasm, and that patient's chances of survival. Thus, the mortality from pediatric cancers can be reduced if tumors are found and treated at an early stage. Moreover, while treatment-related improvements in survival may have resulted in a decline in childhood cancer mortality (50), current treatment protocols can be invasive (surgery) or can produce deleterious side-effects (chemotherapy and radiation). Side-effects are a particular concern in the treatment of pediatric neoplasms because children are still growing: chemotherapy and radiation can interfere with growth, and the consequences can be very serious. Accordingly, it is clear that alternative strategies for diagnosis and treatment of pediatric neoplasms are still needed in order to achieve earlier diagnosis, improve survival in children with cancer, and ease the negative effects of therapy.
The Id proteins are helix-loop-helix transcription factors that have been implicated in the control of cell differentiation (1). In addition to this role in differentiation, Id proteins also have been implicated in cell-cycle control. In particular, the role of Id proteins as positive regulators of cell-cycle progression has been firmly established for one member of the Id family, Id2 (1, 3, 4). Only Id2, and not the other members of the Id-protein family (Id1 and Id3), is able to disrupt the antiproliferative effects of tumor-suppressor proteins of the Rb family (i.e., the ‘pocket’ proteins: Rb, p107, and p130), thereby allowing cell-cycle progression (3, 4).
It is known that Id2 mRNA is overexpressed in neoplastic cells that give rise to pancreatic cancer (46). It has also been shown that Id2 mRNA expression is prominent in certain leukemias (47, 48). However, prior to the present invention, it was not known that Id2 protein is highly expressed in cells of neuroblastomas and other solid pediatric tumors. Moreover, prior to the present invention, it was not known that Id2 mediates signaling by Myc oncoproteins, such that inhibition of Id2 in solid pediatric tumors has an antiproliferative effect.